Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease
Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease
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DOI：
10.1007/s100480050063
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发表时间：
1999-04-01
期刊：
影响因子：
2.2
通讯作者：
Graeber, MB
中科院分区：
文献类型：
--
作者：
Grasbon-Frodl, EM;Kösel, S;Graeber, MB
线粒体编码的 tRNA 基因突变已在多种神经系统疾病中得到描述。其中一种突变，即线粒体 tRNA (Gln) 基因第 4336 位核苷酸处的 A 到 G 转变，与阿尔茨海默病和帕金森病有关。我们现在已经对 20 例经组织学证实的特发性帕金森病病例中的所有 22 个线粒体编码的 tRNA 基因进行了完整的序列分析。从冷冻或福尔马林固定和石蜡包埋的大脑的黑质中提取的基因组 DNA 通过聚合酶链式反应进行扩增，然后进行自动测序。在 1 名患者的 tRNA(Thr) (15950 G/A) 和 tRNA(Pro) (15965 T/C) 基因中分别检测到两个新的同质点突变。限制性内切酶消化显示，96 名对照者和 40 名经神经病理学证实的阿尔茨海默病病例中不存在 15950 G/A 突变。 100 名对照受试者和 47 名阿尔茨海默病病例中显示不存在 15965 T/C 突变。除了这两种新突变之外，在总共 6 名不同患者的 tRNA(Asp) (G7521A, 1)、tRNA(Arg) (T10463C, 1)、tRNA(Leu(CUN)) (A12308G, 2) 和 tRNA(Thr) (A15924G, 1; G15928A, 2)，包括1名携带tRNA(Gln)(A4336G)突变的患者。 G15950A 转变影响 tRNA(Thr) 氨酰受体茎的 70 位，该位置被认为是苏氨酰-tRNA 合成酶的识别元件，并且至少在某些 tRNA 中参与初级线粒体转录物的加工。线粒体 tRNA(Pro) 基因中的 T15965C 点突变改变了 T Psi C 茎的 64 位。细菌氨酰-tRNA 中相应的核苷酸参与与延伸因子 Tu 的相互作用。因此，这两种新突变可能具有功能相关性，并可能导致受影响个体的多巴胺能神经细胞死亡。
Mutations in mitochondrially encoded tRNA genes have been described in a variety of neurological disorders. One such mutation, the A to G transition at nucleotide position 4336 of the mitochondrial tRNA(Gln) gene, has been associated with both Alzheimer and Parkinson disease. We have now performed a complete sequence analysis of all 22 mitochondrially encoded tRNA genes in 20 cases of histologically proven idiopathic Parkinson disease. Genomic DNA extracted from the substantia nigra of frozen or formalin-fixed and paraffin-embedded brains was used for amplification by polymerase chain reaction followed by automated sequencing. Two new homoplasmic point mutations were detected in the genes for tRNA(Thr) (15950 G/A) and tRNA(Pro) (15965 T/C) in 1 patient each. Restriction enzyme digestion revealed absence of the 15950 G/A mutation in 96 controls and in 40 cases of neuropathologically confirmed Alzheimer disease. The 15965 T/C mutation was shown to be absent from 100 control subjects and 47 Alzheimer cases. In addition to the two novel mutations, six known sequence variants were detected in a total of 6 different patients in the genes for tRNA(Asp) (G7521A, 1), tRNA(Arg) (T10463C, 1), tRNA(Leu(CUN)) (A12308G, 2), and tRNA(Thr) (A15924G, 1; G15928A, 2), including 1 patient carrying the tRNA(Gln) (A4336G) mutation. The G15950A transition affects position 70 of the aminoacyl acceptor stem of tRNA(Thr), which has been implicated as a recognition element for threonyl-tRNA synthetase and, at least in some tRNAs, in the processing of primary mitochondrial transcripts. The T15965C point mutation in the mitochondrial tRNA(Pro) gene alters position 64 of the T Psi C stem. The corresponding nucleotide in bacterial aminoacyl-tRNAs is involved in the interaction with elongation factor Tu. Thus, the two novel mutations are likely to be of functional relevance and could contribute to dopaminergic nerve cell death in affected individuals.